Women now constitute one of the fastest growing populations becoming infected with HIV. Drug use plays a major role in the spread of this disease in women and drug abusers are more likely to have neurological complications with HIV infection. In the prior funding period, potential neural mechanisms and target sites for cocaine-HIV interactions in the female brain were identified, leading to the following questions: Are dopaminergic neurochemical systems a preferential target for cocaine+HIV-induced neurotoxicity? And moreover, is the dopamine transporter protein (DAT) a primary target for this cocaine-viral interaction? Recent studies have shown that DAT is reduced in patients with HIV and cognitive deficits, but the mechanisms for this reduction are unknown and current therapeutic strategies unsuccessful. However, dopaminergic systems are known to be responsive to estrogens, and estrogens may provide a unique therapeutic opportunity in women for treatment of HIV-associated cognitive and motor dysfunction. First, the effects of cellular oxidative stress produced by cocaine+Tat/gp120 on monoamine transporters (DAT, NET and SERT) will be determined. We have found that oxidative stress plays an important role in cocaine+Tat/gp120 neurotoxicity and the ability of estrogenic compounds to prevent this stress will be assessed. Second, we will test the ability of estrogen to modulate dopaminergic markers under physiological conditions in female rats exposed to cocaine+Tat/gp120. The function of DAT will be determined using in vivo microdialysis. Third, we will determine whether cocaine+Tat/gp120 produces dopaminergic dysfunction by altering intracellular regulation of DAT signaling mechanisms. Estrogens will be used to modulate intracellular proteins following cocaine+Tat neurotoxicity, providing insight into potential key mechanisms and for developing novel therapeutic strategies. Our gender-based orientation, in combination with HIV protein neurotoxicity, is innovative and will be translational to the important women's health issues of drug abuse and the neurological complications of AIDS. The ultimate goal of this research is to identify the critical neurological targets of HIV infection and to develop innovative pharmacological strategies for preventing cognitive and motor dysfunction following HIV infection in drug abusing women.